The present invention relates to novel substituted piperazines and piperidines and derivatives thereof useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. The novel compounds of the present invention are central nervous system agents. More particularly, the novel compounds of the present invention are dopamine antagonists.
Dopamine (DA) D2 antagonists are established as antipsychotic agents. Undesired consequences of DA D2 antagonism are extrapyramidal side effects and tardive dyskinesia. More recently, the DA D4 receptor has been identified as having a possible role in schizophrenia. The atypical antipsychotic drug clozapine has a tenfold higher affinity for the DA D4 receptor than the D2 (Van Tol H. H. J., Bunzow J. R., Guan H. -C., et al., "Cloning of a human dopamine D4 receptor gene with high affinity for the antipsychotic clozapine." Nature, 1991;350:614-619) and is notable for its lack of extrapyramidal side effects and tardive dyskinesia. The levels of mRNA for the D4 receptor are much higher in the frontal cortex and limbic region, which are associated with cognitive and emotional function, than in the striatum, which is associated with movement (Van Tol, et al., supra, 1991). In addition, Seeman P., Guan H. -C., and Van Tol H. H. M., "Dopamine D4 receptors elevated in schizophrenia," Nature, 1993;365:441-445 has reported a sixfold increase of the D4 recept or number in postmortem specimens from patients with schizophrenia compared to controls.
The compounds of the present invention were shown to selectively bind to the DA D4 receptor while having weak affinity for the DA D2 and DA D3 receptors.
A series of piperazines represented by the Formula I ##STR1## A=CO, COCH.sub.2, COCH.sub.2 CH.sub.2, CH(OH)CH.sub.2 CH.sub.2, COCH.sub.2 CH.sub.2 CH.sub.2, or CH(OH)CH.sub.2 CH.sub.2 CH.sub.2
R=CH.sub.3, 2-(2'-hydroxyethoxy)ethyl, cyclohexyl, benzyl, m-methyl-, or p-t-butylbenzyl, phenethyl, C.sub.6 H.sub.5, o- or p-chlorophenyl, o-, m-, or p-methoxyphenyl, o-, m-, or p-tolyl, 2,6-xylyl, 2-pyridyl, 2-pyrimidyl, or 2-thiazolyl are disclosed by Petigara R. B., et al., Journal of Medicinal Chemistry, 1968;11:332-336 as central nervous system depressants.
A series of arylpiperazines represented by the Formula I ##STR2## wherein R is hydrogen, trifluoromethyl, hydroxy, nitro, halogen, lower alkyl, or lower alkoxy;
R' is hydrogen, trifluoromethyl, halogen, lower alkyl, or low er alkoxy; and
R" is hydrogen or lower alkoxy; or
two of R, R', and R" are lower alkylenedioxy; or an acid addition salt thereof are disclosed in United Kingdom Published Patent Application GB 2,057,441A as having circulation-enhancing activity.
The compounds of the present invention, unlike the compounds disclosed in Petigara R. B., et al., supra, (1968) and United Kingdom Published Patent Application GB 2,057,441A, interact selectively with the DA D4 receptor. Thus, the compounds of the present invention are DA D4 selective antagonists which are useful in the treatment of psychosis such as schizophrenia without the extrapyramidal side effects associated with an agent that interacts with the DA D2 receptor.